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ObjectiveTo assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial.MethodsThere were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model.ResultsPatients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory.ConclusionsIn anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS.Clinical trial registrationARISTOTLE clinical trial numberNCT00412984.

Objective In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients. Methods APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo. Bleeding including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, and any bleeding were analysed using an on-treatment analysis. Kaplan–Meier curves were plotted to describe the timing of bleeding, and a Cox proportional hazards model was used to identify predictors of ISTH major or CRNM bleeding and any bleeding. Median follow-up was 241 days. Results The proportion of patients who experienced TIMI major or minor, ISTH major or CRNM, and any bleeding was 1.5%, 2.2% and 13.3%, respectively. The incidence of bleeding was highest in the immediate post-ACS period (0.11 in the first 30 days vs 0.03 after 30 days events per 1 patient-year); however, >60% of major bleeding events occurred >30 days after the end of the index hospitalisation. Gastrointestinal bleeding was the most common cause of major bleeding, accounting for 45.9% of TIMI major or minor and 39.5% of ISTH major or CRNM bleeding events. Independent predictors of ISTH major or CRNM bleeding events included older age, renal dysfunction, dual oral antiplatelet therapy, smoking history, increased white cell count and coronary revascularisation. Conclusions When compared with placebo, the use of apixaban is associated with an important short-term and long-term risk of bleeding in high-risk post-ACS patients, with gastrointestinal bleeding being the most common source of major bleeding. The baseline predictors of major bleeding appear to be consistent with those identified in lower-risk ACS populations with shorter-term follow-up. Clinical trial No NCT00831441.